1. Field of the Invention
The present invention relates to certain alpha amino, thio, oxo substituted ketone compounds, their salts, hydrates and derivatives thereof, a process for their preparation, intermediates useful in their preparation, and pharmaceutical compositions containing them. Such ketone compounds are inhibitors of phospholipase A2 enzymes that are involved in the human inflammatory diseases and are thus useful agents in the treatment of inflammatory diseases such as asthma, arthritis, inflammatory bowel disease, and neurodegenerative diseases.
2. Background of the Invention and Description of the Prior Art
Inflammatory diseases of the skin, such as psoriasis and atopic dermatitis, afflict greater than 5% of the population. Inflammatory diseases such as asthma affect more than 10 million people in U.S. alone. Currently the treatment of these disorders typically involves the topical and inhalation use of coricosteroids and broncodilators. However, these agents also have undesirable side effects such as skin atrophy which limit the duration of therapy. In addition, topical application of a drug is difficult for many patients where the affected area may be very large.
Phospholipase A2 (PLA2) is the common name for phosphatide 2-acylhydrolase which catalyzes the hydrolysis of the sn-2-acyl ester bond of phosphoglycerides and results in production of lysophospholipids and free fatty acids. When the fatty acid is arachidonic acid, further action by cyclooxygenase and 5-lipoxygenase enzymes results in eicosanoid production, which is implicated in inflammation and leukotrienes which are linked to asthma. Lysophophospholipid metabolism results in production of platelet activating factor and both lysophospholipids and platelet activating factor play a role in inflammation.
PLA2 enzymes exist as secreted forms (MW˜12,000-15,000) and cytosolic forms (MW˜85,000). The cytosolic or cPLA2 enzymes appear to play a key role in the pathway leading to the formation of platelet activating factor and the eicosanoids.
Inappropriate activation of the cytosolic PLA2 enzymes, therefore, can result in a variety of chronic and acute conditions including asthma, cerebral ischemia (Clemens et al, Stroke, 1996, 27, 527-535), Alzheimer's Disease (Stephenson et al, Neurobiology of Stroke, 1996, 3, 51-63 and see also U.S. Pat. No. 5,478,857), rheumatoid arthritis, neutrophil and platelet activation (Huang et al, Mediators of Inflammation, 1994, 3, 307-308), chronic skin inflammation and damage to the skin resulting from exposure to ultraviolet light (Gresham, et al., American Journal of Physiology, 1996, 270; Cell Physiology 39:C1037-C1050) and macrophage activation (Balsinde, et al., Journal of Biological Chemistry, 1996, 271, 6758-6765).
Inhibitors of the cPLA2 enzymes may, therefore, be of use in controlling a wide variety of inflammatory diseases. The literature describes a significant number of compounds said to be phospholipase A2 inhibitors.
Biochemistry (1993) 32: 5935-5940, discloses a trifluoromethyl ketone analog of arachidonic acid having the formula as a selective inhibitor of cPLA2.
Bioorganic Med. Chem. Lett. (1995) 5: 519-522, discloses selective cPLA2 inhibitors of the formula where R is either H or OH.
Japanese published Patent Application JP09268153A (Derwent No. 97-554679/51) discloses cPLA2 inhibitors of the formula RCOCF3 where RCO is an acyl residue of an n-3 series highly unsaturated fatty acid. The compounds are said to be useful as antiinflammatory or anti-allergic drugs.
Certain trifluoromethylketone have been disclosed as inhibitors of fatty acid amide hydrolase in Bioorg. & Med. Chem. Lett. (1999) 9, 265-270.
Published PCT Application WO 98/25893 discloses arylsulfonamide compounds of the general formula wherein                A represents a C4-C10 alkyl group, an aryl group, an arylalkyl group, radicals selected from the group consisting of —CH═CH—B, —O—B, —S—B, and —NH—B, or radicals of formula —CH2—X,wherein        B represents a non-aromatic C3-C8 carbocycle, a C3-C8 alkyl group, a heterocycle or an arylalkyl group, each of which is optionally substituted with one or more members independently selected from the group consisting of a halogen atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, cyano, nitro, a heterocycle, an aryl group and an aryloxy group, and        X is a member selected from the group consisting of a halogen atom, —S-aryl, —S-heterocycle, and —PO3R2 wherein each R is independently selected from the group consisting of a hydrogen atom and C1-C3 alkyl;        R1 and R2 each independently represent a hydrogen atom, a lower alkyl group, or a group represented by the formula: —(CH2)q—A′ wherein q is an integer of 2 to 4, and A′ is a member selected from the group consisting of a hydroxyl group, a group represented by the formula:         wherein R5 and R6 each independently represent a hydrogen atom, a lower alkyl group, or a group represented by the formula:         wherein R7 represents a hydrogen atom, a lower alkyl group, or a group represented by the formula:         wherein s is an integer of 2 to 5; or        R1 and R2 each independently represent an unsubstituted cycloalkyl group, or a cycloalkyl substituted with a lower alkyl or halogen or condensed with an aromatic ring, a bicycloalkyl, or tricycloalkyl, said bicycloalkyl or tricycloalkyl being an aliphatic saturated hydrocarbon group made of two or three rings, respectively, with at least two carbon atoms being common to each ring, or an azabicycloalkyl group which is a bicycloalkyl group as described above in which one carbon atom is replaced by a nitrogen atom or a group represented by the formula:         wherein g and h are each an integer of 1 to 4, and B′ stands for a lower alkyl group, an arylalkyl group, an arylalkyl group substituted by lower alkyl; halogen or a lower alkoxy group, or a pyridylalkyl group, or a pyridylalkyl group substituted with a lower alkyl group, a halogen or a lower alkoxy group; or        R1 and R2 may be combined together to form a 6- or 7-membered ring which may contain a nitrogen or oxygen atom in addition to the nitrogen atom to which R1 and R2 are bonded, and said 6- or 7-membered ring may be substituted with a lower alkyl, arylalkyl, cycloalkylalkyl or heteroarylalkyl group;        R3 represents a hydrogen atom, a lower alkyl group, or a C3-C8 cycloalkyl group;        R4 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom;        n is an integer of 1 to 4, provided that when n is 2, the two R4 groups may form a cyclohexenyl or phenyl ring together with two adjacent carbon atoms constituting the benzene ring; and any pharmacologically acceptable salts thereof as inhibitors of phospholipase A2 activity, particularly cPLA2.        
The published PCT Application WO 98/08818 discloses Inhibitors of phospholipase enzymes of formulae I, II and III. or a pharmaceutically acceptable salt thereof, wherein:                A is independent of any other group and is selected from the group consisting of —CH2— and —CH2—CH2—;        B is independent of any other group and is selected from the group consisting of —(CH2)n—, —(CH2O)n—, —(CH2S)n—, —(OCH2)n—, —(SCH2)n—, —(CH═CH)n—, —(C≡C)n—, —CON(R6)—, —N(R6)CO—, —O—, —S— and —N(R6)—;        R1 is independent of any other R group and is selected from the group consisting of —X—R6, —H, —OH—, halogen, —CN, —NO2, C1-C5 alkyl, alkenyl, alkynyl, aryl and substituted aryl;        R2 is independent of any other R group and is selected from the group consisting of —H, —COOH, —COR5, —CONR5R6, —(CH2)n—W—(CH2)m—Z—R5, —(CH2)n—W—R5, —Z—R5, C1-C10 alkyl, alkenyl and substituted aryl;        R3 is independent of any other R group and is selected from the group consisting of —H, —COOH, —COR5, —CON R5R6, —(CH2)n—W—(CH2)m—Z—R5, —(CH2)n—W—R5, —Z—R5, C1-C10 alkyl, alkenyl and substituted aryl;        R4 is independent of any other R group and is selected from the group consisting of —H, —OH, OR6, SR6, CN, —COR6, —NHR6, —COOH, —CONR6R7, —NO2, —CONHSO2R8, C1-C5 alkyl, alkenyl and substituted aryl;        R5 is independent of any other R group and is selected from the group consisting of —H, —OH, —O(CH2)nR6, —SR6, —CN, —COR6, —NHR6, —COOH, —NO2, —COOH, —CONR6R7, —CONHSO2R8, C1-C5 alkyl, alkenyl, alkynyl, aryl, substituted aryl, —CF3, —CF2CF3 and         R6 is independent of any other R group and is selected from the group consisting of —H, C1-C5 alkyl, alkenyl, alkynyl, aryl and substituted aryl;        R7 is independent of any other R group and is selected from the group consisting of —H, C1-C5 alkyl, alkenyl, alkynyl, aryl and substituted aryl;        R8 is independent of any other R group and is selected from the group consisting of C1-C3 alkyl, aryl and substituted aryl;        R9 is independent of any other R group and is selected from the group consisting of —H, —OH, a halogen, —CN, —OR6, —COOH, —CONR6R7, tetrazole, —CONHSO2R8, —COR6, —(CH2)nCH(OH)R6 and —(CH2)nCHR6R5;        R10 is independent of any other R group and is selected from the group consisting of —H, —OH, a halogen, —CN, —OR6, —COOH, —CONR6R7, tetrazole, —CONHSO2R8, —COR6, —(CH2)nCH(OH)R6 and —(CH2)nCHR6R5;        W is, independent each time used including within the same compound, selected from the group consisting of —O—, —S—, —CH2—, —CH═CH—, —C≡C— and —N(R6)—;        X is independent of any other group and is, independently each time used including within the same compound, selected from the group consisting of —O—, —S— and —N(R6)—;        Z is independent of any other group and is, independently each time used including within the same compound, selected from the group consisting of —CH2—, —O—, —S—, —N(R6)—, —CO—, —CON(R6)— and —N(R6)CO—;        m is, independently each time used including within the same compound, an integer from 0 to 4; and        n is independently of m and is, independently each time used including within the same compound, an integer from 0 to 4.        
Drugs 1998, Vol. 1, No. 1, pp. 49-50 discloses a limited series of cPLA2 inhibitors as shown below
R1R2XCH3 (1) (1) (1)CH3(CH2)9— CH3(CH2)9— Ph(CH2)5 CH3(CH2)9—O O S SO2
U.S. Pat. No. 5,866,318 relates to methods for inhibiting cell death in mammalian cells, particularly in neuronal cells, by administering a suitable inhibitor of phospholipase A2 activity, typically an inhibitor of cPLA2.
WO 97/21676 Patent discloses certain azetidinone compounds as phospholipase inhibitors in the treatment of atherosclerosis.
U.S. Pat. No. 5,453,443 discloses a series of biaryl ketones which are reported to inhibit PLA2 enzymes. These compounds have the generic formula wherein:                R1 is selected from                    (a) hydrogen,            (b) —C1-6 alkyl, and            (c) —C1-6 alkyl-phenyl;                        or wherein R1 and R5 are joined such that together with the carbon atoms to which they are attached there is formed a saturated or unsaturated carbon ring of 3, 4, 5, 6, 7 or 8 atoms;        R2 and R3 are each independently selected from                    (a) hydrogen,            (b) —C1-6 alkyl, and            (c) —C1-6 alkyl-phenyl;                        or wherein two R2 or two R3 are joined such that together with the carbon atoms to which they are attached there is formed a saturated or unsaturated carbon ring of 3, 4, 5, 6, 7 or 8 atoms;        R5 is as defined above or is selected from                    (a) hydrogen            (b) —C1-6 alkyl,            (c) —C1-6 alkyl-phenyl C1-6 alkyl,            (d) —OH,            (e) —O—C1-6 alkyl, or            (f) —C1-6 alkyl-phenyl C1-6 alkyl;                        R6 is selected from                    (a) hydrogen            (b) —C1-6 alkyl, and            (c) —C1-6 alkyl-phenyl, wherein the phenyl is optionally substituted with C1-2 alkyl;            (d) —OH,            (e) —O—C1-6 alkyl, or            (f) —O—C1-6 alkyl-phenyl, wherein the phenyl is optionally substituted with C1-2 alkyl;                        or wherein two R6 are joined to form O═ or are joined together such that together with the carbon atom to which they are attached there is formed a saturated or unsaturated carbon ring of 3, 4, 5, 6, 7 or 8 atoms;        R8, R9 and R14 are each independently selected from                    (a) H,            (b) —C1-6 alkyl,            (c) halo            (d) —CN,            (e) —OH,            (f) —OC1-6 alkyl,            (g) —OC1-6 alkyl-phenyl,            (h) —SR11,            (i) S(O)R11, or            (j) S(O)2R11;                        R10, R15, R16 and R17 are each independently selected from                    (a) hydrogen,            (b) —C1-6 alkyl, and            (c) —C1-6 alkyl-phenyl;                        R11 is selected from                    (a) —C1-6 alkyl,            (b) —C2-6 alkenyl,            (c) —CF3,            (d) -phenyl(R12)2, or            (e) —C2-6 alkenyl-phenyl(R12)2,                        R12 is                    (a) hydrogen,            (b) —C1-6 alkyl,            (c) Cl, F, I or Br;                        R13 is perfluoroC1-6alkyl;        A and B are each independently                    (a) covalent bond,            (b) O,            (c) S,            (d) S(O), or            (e) S(O)2;                        Q is selected from                    (a) —CH(OH)R13,            (b) —COR13,            (c) —COR16, or            (d) —C1-6 alkylCOCOOR17;                        X1 is selected from                    (a) —O—,            (b) —S—,            (c) —S(O)—,            (d)                        Z is                    (a) H, or            (b) -phenyl-(R14)3,                        m is 0, 1, 2, 3 or 4;        n is 2, 3, 4, 5, 6 or 7; and        r and s are each independently 0, 1, 2, 3, 4, 5, 6, 7 or 8.        
Published application WO 99/15129 discloses selective cPLA2 inhibitors having the formula                 wherein W is CH═CH, CH═N, O or S;        R1 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkylthio, halo, hydroxy, cyano,          in which R2 and R3 are each independently hydrogen or (C1-C6)alkyl, —COO—(C1-C6)alkyl, CF3, (C1-C6)alkylphenyl, phenyl or phenyl substituted by one or more, preferably 1-3, of (C1-C6)alkyl, —COO—(C1-C6)alkyl,          in which R2 and R3 are as defined above, halo, hydroxy, —O—(C1-C6)alkyl, —S—(C1-C6)alkyl or (C2-C6)alkenyl;        p is 0, 1 or 2;        A is V—(Rc)n—;        Rc is a straight or branched chain alkyl group;        n is 0 or an integer of from 1 to 6;        Ra and Rb when taken together form an oxo (═O) group, or Ra and Rb are each independently hydrogen or OH;        V is O, —S—, —SO—, —SO2, —CONH or NHCO when n is an integer of from 1 to 6 or V is (C2-C6) alkenyl or a bond when n is 0 or an integer of from 1 to 6;        D is —(CH2)m or a bond linking the          ring to Y;        m is an integer of from 1 to 6;        Y is —O—, —S—, —SO—, —SO2;          or a bond;        R4 is as defined below for R7;        Z is         in which B is:         X is S or O;        q is an integer from 1 to 6;        R9 is hydrogen or (C1-C6)alkyl;        R10 is hydrogen, CN, NO2, OH, —O—(C1-C6)alkyl, (C1-C6) alkyl, phenyl or (C1-C6)alkylphenyl;        R5 and R6 are each independently hydrogen or (C1-C18) alkyl;        R7 and R8 are each independently                    (a) hydrogen;            (b) (C1-C18)alkyl;            (c) (C1-C18)alkyl substituted by one or more of                            (1) phenyl;                (2) phenyl substituted by 1-5 fluoro, 1-3 (for each of the following phenyl substituents) halo (other than fluoro), 1-3 (C1-C6)alkoxy, 1-3(C1-C6)alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C1-C6)alkylthio, amino, 1-3 (C1-C6) alkylamino, di(C1-C6)alkylamino, —CO2H, —COO—(C1-C6)alkyl, —SO3H, —SO2NHR15 in which R15 is hydrogen or (C1-6)alkyl, or                  in which R2 and R3 are as defined above;                (3) heterocyclic selected from oxadiazolyl, isoxazolyl, oxazolyl, furyl and thiazolyl;                (4) heterocyclic substituted by one or more of, preferably 1-3, phenyl, phenyl substituted by 1-3 (for each of the following) halo, (C1-C6)alkoxy, (C1-C6)alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C1-6)alkylthio, amino, (C1-C6)alkylamino, di(C1-C6)alkylamino, CO2H, —OO—(C1-C6)alkyl, —SO3H, SO2NHR15 in which R15 is hydrogen or (C1-C6)alkyl, or                  in which R2 and R3 are as defined above, (C1-C6)alkyl or (C1-C6)alkyl substituted by one or more, preferably 1-3, phenyl or heterocyclic groups, said phenyl or heterocyclic group being unsubstituted or substituted by 1-3 (for each of the following) halo, 1-3 (C1-C6)alkoxy, 1-3 (C1-C6)alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C1-C6)alkylthio, amino, 1-3 (C1-C6)alkylamino, di(C1-C6)alkylamino, COOH, —COO—(C1-C6)alkyl, —SO3H, —SO2NHR15 in which R15 is hydrogen or (C1-C6)alkyl, or                  in which R2 and R3 are each independently hydrogen or (C1-C6)alkyl, the heterocyclic radical being selected from imidazolyl, oxadiazolyl, isoxazolyl, pyrrolyl, pyrazolyl, oxazolyl, furyl, thianyl or thiazolyl;                (5) carboxy or —COO—(C1-C6)alkyl;                (6) hydroxy, halo, —O—(C1-C6) alkyl or —S—(C1-C6)alkyl, with the proviso that the OH, ethers or thioethers cannot be on the carbon bearing the heteroatoms;                (7) cyano;                (8) halo, trifluoromethyl or trifluoroacetyl;                (9) CH2 L—R16 in which L is                  or —O—SiR16R18R19 or a bond in which R16 and R17 are each independently (C1-C18)alkyl or (C2-C18)alkenyl or (C1-C18)alkyl or (C2-C18)alkenyl substituted by one or more, preferably 1-3, phenyl or heterocyclic radicals, said phenyl or heterocyclic radicals being unsubstituted or substituted by 1-5 fluoro, 1-3 halo (other than fluoro), 1-3 (C1-C6)alkoxy, 1-3(C1-C6)alkyl, nitro, cyano, hydroxy, 1-3 trifluoromethyl, 1-3 (C1-C6)alkylthio, amino, 1-3(C1-C6)alkylamino, 1-3 di(C1-C6)alkylamino, CO2H, 1-3 —COO(C1-C6)alkyl,                  or —SO2NHR9 in which R9 is hydrogen or (C1-C6)alkyl and R2 and R3 are as defined above;                                                 in which B1 is          —SO2—, —PO(OR9)2 or a bond; providing that when B1 is —PO(OR9)2, then R7 becomes R9, and when B1 is          or —SO2—, then R7 cannot be hydrogen;        X, q, R5, R6, R7, R8, R9 and R10 are as defined in (a);         in which q, R5 and R6 are as defined above;        R18, R19 and R11 are as defined above for R7 and R8 except that they may not be hydrogen, or R18 and R19 taken together with the nitrogen to which they are attached represent a 4, 5- or 6-membered heterocyclic ring and Y, R7 and R11 are as defined above, or R18, R19 and R11 taken together with the nitrogen to which they are attached represent pyridinium, said pyridinium group being unsubstituted or substituted by (C1-C12)alkyl, (C1-C12)alkoxy, amino, (C1-C12)alkylamino, di(C1-C12)alkylamino,          in which R2 and R3 are as defined above, phenyl or phenyl (C1-C10)alkyl;         in which R13 is (C1-C18)alkyl or (C1-C18)alkyl substituted by carboxy,          in which R2 and R3 are as defined above, hydroxy, —O—(C1-C6) alkyl, —O—(C1-C6) alkyl or —S—(C1-C6) alkyl substituted by 1 or 2 phenyl or substituted phenyl groups, the substituents for the substituted phenyl groups being 1-5 fluoro or 1-3 (for each of the following phenyl substituents) halo (other than fluoro), (C1-C6)alkoxy, (C1-C6)alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C1-C6)alkylthio, amino, (C1-C6) alkylamino, di(C1-C6) alkylamino, CO2H, COO—(C1-C6) alkyl, SO3H, SO2NHR15 in which R15 is hydrogen or (C1-C6) alkyl or          in which R2 and R3 are as defined above;        r is 0 or an integer of from 1 to 3;        R7 is as defined above;        M is —(CH2—)mT where T is          in which R2 is as defined above, —SO2— or a bond when MR7 is on nitrogen and providing that when T is          or —SO— or —SO2—, then R7 cannot be hydrogen, and T is          or a bond when MR7 is on a carbon atom of the heterocyclic ring;        R14 is hydrogen or (C1-C6)alkyl;        m is 0 or an integer of 1-6;         wherein Q is —O—, —S—, —SO— or —SO2—, and q, R5, R6 and R7 are as defined above, providing that when Q is —SO— or —SO2—, R7 cannot be hydrogen;                    (f) R7 wherein R7 is defined above, providing that when Y is —SO— or —SO2—, R7 cannot be hydrogen; and                        R18 and R19 are phenyl or phenyl substituted by 1-3 halo, (C1-C6)alkoxy, (C1-C6)alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C1-C6)alkylthio, amino, (C1-C6)alkylamino, di(C1-C6)alkylamino, CO2H, —COO—(C1-C6)alkyl, —SO3H, SO2NHR15 in which R15 is hydrogen or (C1-C6)alkyl, or          in which R2 and R3 are as defined above; or pharmaceutically acceptable salts, solvates or prodrugs thereof.        R18 and R19 are phenyl or phenyl substituted by 1-3 halo, (C1-C6)alkoxy, (C1-C6) alkyl, nitro, cyano, hydroxy, trifluoromethyl, (C1-C6) alkylthio, amino, (C1-C6) alkylamino, di(C1-C6)alkylamino, CO2H, —COO—(C1-C6)alkyl, —SO3H, SO2NHR15 in which R15 is hydrogen or (C1-C6)alkyl, or          in which R2 and R3 are as defined above; or pharmaceutically acceptable salts, solvates or prodrugs thereof.        
There is nothing in any of the foregoing references, or in the general prior art, to suggest the novel alpha-amino, thio, oxo substituted ketones of the present invention as cytosolic phospolipase A2 inhibitors.